Drug Interactions with Hyperbaric Oxygenation - … 9 Drug Interactions with... · Drug...
Transcript of Drug Interactions with Hyperbaric Oxygenation - … 9 Drug Interactions with... · Drug...
Drug Interactions withHyperbaric Oxygenation
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Chapter 982
Oxygen as a Drug
When oxygen is breathed in concentrations higher thanthose found in the atmospheric air, it is considered to be a
drug. By this definition, wperbaric oxygen (HBO) is definitelya drug and it can iriteract with other drugs. It is important to be aware of th~se interactions in patients whoare receiving other qrugs, for HBO can either potentiate orreduce the 'effectsof other drllgs. Conversely, there are alsodrugs that reduce or potentiate the effects of HBO. Thesecorrespond to protectors :lgainst and enhancers of oxygentoxicity, respectively, as d:scussed in Chapter 6.
Many drugs, including nonprescription drugs, have undesirable'side effects that may be modified in the hyperbaric environment. Some drug effects are potentiated andsome are antagonized; some agents produce entirely different effects than those observed in normobaric environments.
Drugs Affecting the Central NervousSystem (CNS)
Anesthetics. The interactions of anesthetics with HBO is
discussed Chapter 38, but some of the drugs used are reviewed briefly here, due to their importance in many aspects of the current topic.
CNS Stimulants. CNS st~mulants such as amphetaminesinteract unfavorably with ~-:IBO.And, notably, excessivecoffee drinking in those who are susceptible to caffeine mayalso predispose to oxygen toxicity.
Ethanol. Hyperbaric air has a synergistic effect with ethanol and increases the sleeping time in mice. This may explain the increased susceptibility to the effects of compression and decompression of those who have imbibed alcohol. There are no special ill effects ofHBO on patients whosuffer carbon monoxide poisoning while they are inebriated. There is no evidence that HBO accelerates the metab
olism of "sobering up" in alcoholics.,
Narcotic Analgesics. Narcotic drugs generally depress respiration by reducing the leactivity of medullary centers toCO2• This, combined wid: the depressing effect of HBO onrespiration, can lead to a Ese in paC02, which causes vasodilatation and enhaJilcesdxygen toxicity.
Pharmacokinetics of meperidine in dogs breathing air at1 ATAis not altered undf:r HBO at 2.8 ATA,or breathingair at 6 ATA.The findin~s in dogs cannot, of course, beextrapolated to humans, as the two species handle drugsvery differently. The actioil of morphine also is unchangedby HBO.
Pentobarbital. It has been mentioned in Chapter 3 thatpentobarbital anesthesia can be reversed in rats under atmospheric pressure. Attempts to distinguish between thetwo possible causes of this reversal - changes in the drugdisposition and changes in drug-receptor interaction- bystudying the pharmacokinetics of pentobarbital in dogs exposed to HBO shows no significant effect of HBO on totalplasma clearance, volume of distribution, or eliminationhalf-life of pentobarbital. This rules out changes in drugdisposition as a cause of reversal of central nervous system(CNS) depression by pentobarbital.
Scopolamine. This is an anticholinergic compound usedwidely for management of motion sickness and may beused concomitantly with HBO, particularly in divers. Bitterman et al (1991) tested the interaction of scopolaminewith HBO at 5 ATAin rats. The duration of the latent period preceding the onset of hyperoxic convulsions was notaltered. However, the visual and cardiovascular side effectsof the drug should be taken into consideration when scopolamine is used in combination with HBO.
Interaction of HBO with Various Drugs
Antimicrobials
HBO increases the permeability of the blood-brain barrier (BBB), as described in Chapter 2. This has led to theinvestigation of HBO as an enhancer of the penetration
of some antibioti<;s a.c~ossthe BBB into the cerebrospinalfluid (CSF) in order to increase their.,effectiveness in men-ingitis. ' ','
Aminoglycoside'N1tj~iflt~CS.Gs,P /jrapsfer of the aminoglycoside antibiotictl:~l(rt¥llycintis not.loalteredunder HBO inrabbits, and HBO has no· significant effect on the CSF concentration of this agent. CO2, which is known to damageBBB, more than doubles the CSF:blood ration for tobramycin. Pharmacokinetics of gentamicin does not change inhealthy volunteers exposed to HBO.
Sulfonamides. Increase o£ oxygen tension has a synergisticbactericidal effect with sulfonamides rather than the usual
bacteriostatic action. HBO and al1tibiotic synergism arediscussed in Chapter 13. \
Mafenide acetate (Sulfamylon), an antibaqerial agentused in burn patients, is a carbonic anhyprase inhibitorand tends to promote CO2 retention and vasodilatation.This substance must be removed from patients beforethey are placed in a hyperbaric chamber for HBO treatment.
Drug Interactions with Hyperbaric Oxygenation
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Antineoplastics .
The role of HBO in enhancing cancer radiosensitivity isdiscussed in Chapter 36.. Interaction of HBO with someahtineoplastic agents will be described here.
Exposure of cancer cells to HBO at 3 ATAfor 2 h produced 'inhibition of DNA synthesis or mitosis. Simultaneous'.exposure to HBO and adriamycin results in decreasedcytotoxicity. However, exposure to adriamycin 2-8 h beforeor after HBO produces an increase in the drug effect. Cytotoxicity increases when cells were exposed to HBO before, during, or after nitrogen mustard administration.
HBO enhances the chemotherapeutic effect of doxorubicin both in cell culture 'and in the rat ,model (Petre et al2003). HBO reciuc~stM!~hte at misori',dazo'remetabolism,, II J , .. , , I • I· .
thus increasing the concentration of this' substance in tu-mors, which enhances radiosensitivity. However, doxorubicin is regarded as a contraindication for concomitant usewith HBO therapy beduse of the increased risk of cardio-I. 'toxicity. An experimental study has shownb that HBO ex-posure does not potentiate doxorubicin-induced cardiotoxicity in rats, but confers cardioprotection against doxorubicin, which warrants further investigation (Karagoz etaI2008).
Cardiovascular Drugs
Adrenomimetic, Adrenolytic, and Ganglion-BlockingAgents. Under HBO, there is a considerable reduction ofhypotensive effect of (J.- and ~-blockers, ganglion blockers,and b-adrenomimeti~s, and elimination of the effects ofcentral adrenomimetics. The pressor effects of the directlyand particularly of the indirectly acting a-adrenomimetics,as well as the cardiotropic effects of ~-adrenoblockers, arepotentiated. Therefore, these drugs should be given afterbut not before the HBO session.
Digitalis/Digoxin. HBO has been reported to decrease theeffectiveness of cardiac glycosides. There is some evidencethat HBO may reduce the toxic effects of digitalis.
Antianginal drugs. The effect of a single HBO session(1.5 ATA,duration 40 min), in combination with antianginal drugs, has been investigated in patients with ischemicheart disease and angina pectoris of effort, NYHA functional class II-III. HBO reduces the degree of indirecthemodynamic effect of nifedipine, potentiates negativechronotropic, and inotropic effects of propranolol - buthas no impact on the degree of hemodynamic effect of depot-glycerol trinitrate.
Heparin. Heparin-treated animals exposed to HBO-Jevelop pulmonary hemorrhages as a result of interactions ofthe anticoagulant effect of heparin and oxygen-induced
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pulmonary lesions. The pressures and exposure times inexperimental studies are much longer than those used clinically and these observations are not applicable to humans.However, since heparin has been used as an adjunctivemeasure in patients undergoing HBO treatments, this potential complication should be kept in mind, althoughnone has been reported in patients on heparin undergoingHBO treatments.
Interaction of HBO with Miscellaneous Drugs
Insulin. The dosages of insulin required in diabetes are decreased during HBO therapy and should be readjusted.
ILosartan. Addition of HBO therapy to losartan, anangiotensin receptor blocker, inci'eases the drug efficacyand has significant benefits in the management of proteinuria (Yilmaz et aI2006).
Reserpine and Guanethidine. Reserpine and guanethidinehave been shown to interact unfavorably with HBO.
Salicylates. There is a significant increase in salicylateclearancein dogs at 2.8 ATA.There are no studies in humans.
Theophylline. There are no effec\>sof HBO (2.8 ATA)onthe pharmacokinetics of theophylline in the dog. There areno studies in humans.
Practical Considera~ions of DrugAdministration During HBO Therapy
The mechanical effect of the pressure on the drug containers should be taken into consideration. Drugs stocked in amultiplace chamber and subjected to repeated compression and decompression should be put into pressure-proofcontainers. There are no problems of explosion with smallvials when pressures are below 3 ATA.Multidose rubbertop vials should be used only once in a hyperbaric chamberbecause of possible contamination while withdrawing adrug. Precautions for intravenouS' infusions are discussedin Chapter 7.
Drugs that Enhance Oxygen Toxicity
Acetazolamide. Acetazolamide is a carbonic anhydrase inhibitor that prevents oxygen-induced vasoconstriction andincreases blood flow under HBO. This predisposes the
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brain to the toxic action of oxygen. Acetazolamide shouldnot be used at pressures greater than 2 ATA.
CNS Stimulants. See section on CNS drugs.~.
Disulfiram. This drug is used in alcohol aversion therapy.It may potentiate oxygen toxicity via in vivo reduction todiethyldithiocarbamate and subsequent inhibition of superoxide dismutase.
Thyroid Extract. Thyroid or thyroid extract given to experimental animals under HBO enhances the toxic effects of
oxyg~n. The increase of metabolic rate is thought to predispose to oxygen-induced convulsions. It is a reasonableassumption that this would also occur in humans).
Drugs that Protect Against OxygenToxicity
This topic has been discussed in Chapter 6 and a list ofdrugs that protect ag~inst oxygen toxicity is given in Table6.6.
Anticonvulsants. Phenytoin (Dilantin) and diazepam (Valium) are used to prevent seizures, and do not have any protective effect against oxygen toxicity as such. Barbituratesare also used as antiepileptics, and may have a protectiveeffect against oxygen toxicity. But the disadvantage of usingbarbiturates is that they are respiratory depressants. Diazepam (Valium) is used to prevent and control seizures ofnonhyperbaric origin. The dosage is 5-50 mg given slowlyby intravenous injection. It may also lead to respiratory depression. Lorazepam is similar in action to diazepam butrequires one-fifth the dose. If phenytoin is used, careshould be taken not to use high pressuJlesof oxygen for longperiods: CNS toxicity may occur without the warning signsof seizures. Carbamazepine has been found to be useful forthe prevention of CNS toxicity during HBO therapy of epilepsy-prone patients.'
Ergot Derivatives. Two ergot derivatives lisuride and quinpirole have been shown to antagonize convulsions in miceinduced by HBO at 5 ATA.This protection was found toabout 50% of that obtained by diazepam. There isno reportof use of any ergot derivatives in patients for this purpose.
Magnesium. Mg ion compounds are substances with antioxidant and vasodilating effects and therefore reduce oxygen toxicity. A single dose of 10 mmol of magnesium sulfate can be given 3 h before a HBO session.
Phenothiazines. Chlorpromazine is considered to be protective against oxygen toxicity.
Propranolol. L-propranolol has been shown to protectmice against HBO-induced seizures (Levy et al 1976).
There have been no reports of clinical application of thiseffect.
Vitamin E. Vitamin E is believed to protect against oxygentoxicity by counteracting the oxygen free radicals. A,doseof 400 mg daily should be given to patients scheduled forHBO therapy starting 2 days before the therapy.
Conclusions
Drug interactions with HBO represent an important subject, but there is a lack of studies for many of the commonlyused medications. Animal studies cannot alwaysbe appliedto humans. Therefore, studies of the pharmacokinetics ofcommonly used drugs in patients receiving HBO should becarried out and an autl10rItative drug incompatibility listcompiled; such a list would be incorporated in variouspharmacopoeia.s f1T\il displayed in hyperbaric treatment fa-.", .
cilities. A di'r~f\ll.historY' shoukli be 'taken of drug use bypatieI(ts and caution 'should be exer6sed in the use of drugsknown to interact with oxygen. '
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